Age-related decline in peak oxygen uptake: Cross-sectional vs. longitudinal findings. A review

Cardiorespiratory fitness is established as an important prognostic factor for cardiovascular and general health. In clinical settings cardiorespiratory fitness is often measured by cardiopulmonary exercise testing determining the gold-standard peak oxygen uptake (VO2peak). Due to the considerable impact of age and sex on VO2peak, results from cardiopulmonary exercise testing are typically assessed in the context of age- and sex-specific reference values, and multiple studies have been conducted establishing reference materials by age and sex using cross-sectional designs. However, crossectional and longitudinal studies have shown somewhat conflicting results regarding age-related declines of VO2peak, with larger declines reported in longitudinal studies. In this brief review, we compare findings from crossectional and longitudinal studies on age-related trajectories in VO2peak to highlight differences in these estimates which should be acknowledged when clinicians interpret VO2peak measurements repeated over time.

Cardiorespiratory fitness is established as an important prognostic factor for cardiovascular and general health. In clinical settings cardiorespiratory fitness is often measured by cardiopulmonary exercise testing determining the gold-standard peak oxygen uptake (VO 2peak ). Due to the considerable impact of age and sex on VO 2peak , results from cardiopulmonary exercise testing are typically assessed in the context of age-and sex-specific reference values, and multiple studies have been conducted establishing reference materials by age and sex using cross-sectional designs. However, crossectional and longitudinal studies have shown somewhat conflicting results regarding age-related declines of VO 2peak , with larger declines reported in longitudinal studies. In this brief review, we compare findings from crossectional and longitudinal studies on age-related trajectories in VO 2peak to highlight differences in these estimates which should be acknowledged when clinicians interpret VO 2peak measurements repeated over time.
Cardiorespiratory fitness (CRF) is established as a powerful marker of present and future health, with higher levels associated with a reduced risk of not only cardiovascular disease and mortality, but also a plethora of other diseases [1][2][3]. Studies employing machine-learning have shown that age and CRF are the two features with greatest impact on mortality prediction in cardiac rehabilitation settings, outperforming commonly used variables from clinical practice [4]. Still, the potential clinical value of CRF in patient follow-up and preventive settings has received little attention, leading to an initiative from the American Heart Association advocating to increase the uptake of CRF assessment in clinical practice [3]. CRF can be estimated by several methods, including non-exercise methods, but the gold-standard method is direct measurement of peak oxygen uptake (VO 2peak ) by ventilatory gas-analysis during dynamic exercise to voluntary exhaustion [5].
Already in 1938, in a comprehensive work of experimental studies of physical fitness in relation to age, Robinson described that "the mechanism for supplying and utilizing O 2 in exhaustive work are only about 50 per cent as effective in a man of 75 as in a boy of 17" [6], hence underscoring the importance of considering age when assessing fitness levels. Together with age, both sex and exercise training status are key determinants of CRF, but still age alone explains 30-40% of variation [7,8]. Using age-adjusted reference data is therefore necessary, and a wide variety of studies have published reference data on VO 2peak by age and sex over the last couple of decades [9,10]. Comparing with a reference standard is necessary to accurately interpret individual patients' fitness levels in clinical settings. However, considerable variation in the age-related decline of VO 2peak has been reported when comparing studies of crossectional and longitudinal designs, as previously discussed by Hawkins and Wiswell [11]. In the years since that publication a plethora of studies have been published, including large studies assessing longitudinal declines by different age-groups.
Still, the age-related decline in fitness is generally referred to be ~10% per decade, even though this is a simplification, and may be grossly inaccurate as will be discussed. Therefore, in this brief review we overview the current literature and compare findings from crosssectional and longitudinal studies on age-related trajectories in VO 2peak . We highlight differences, and show how these differences may be of importance when performing long-time patient follow-up and when interpreting repeated VO 2peak /CRF measurements over time. Relevant studies were identified using structured searches in PubMed and by further review of references in the identified publications of interest.

Age-related declines in cross-sectional studies
Over the last decades a number of studies have reported reference data on VO 2peak by age from cross-sectional studies. Meta-analyses in men have shown annual declines of 0.40 mL/kg/min for both active and sedentary men [12], and 0.44 and 0.35 mL/kg/min for active and sedentary women, respectively, thus assuming linear declines [13]. Similarly, a wide variety of regression equations for predicting VO 2peak by age and sex have been published as previously summarized in extensive reviews [9,10], typically reporting declines between 0.3 and 0.5 mL/kg/min per year. In line with this the expected decline in VO 2peak is generally accepted to be linear and about 10% per decade [11], although some reports have highlighted geographical differences and nonlinear declines [14]. Notable studies from several countries reporting directly measured VO 2peak by gas-analysis during maximal exercise is shown in Fig. 1 and Table 1 [8,[15][16][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][33][34], indicating more or less constant (linear) declines. The age-related declines are similar across both cycle ergometry and treadmill exercise, although values from treadmill exercise are generally higher [34]. Although the baseline fitness level decreases with higher age, meaning that percentage decline increases, most studies still have reported declines of 10-15% in older age-groups as well [8,15,16,21,[23][24][25]32,33].

Age-related declines in longitudinal studies
Quite a few studies have reported longitudinal data on VO 2peak , although most have had relatively few participants, narrow selection criteria, a limited age-span, and importantly, data have not been reported stratified by age groups. Generally, it should be noted that cross-sectional studies typically have reported data on several thousands of participants, while longitudinal studies have smaller sample sizes in the tens or hundreds (Table 1, Table 2). Age-related longitudinal declines from several notable studies are summarized in Fig. 2 [16,[35][36][37][38][39][40][41][42][43][44][45][46][47][48][49][50]. The studies by Fleg et al. including 375 women and 435 men from the Baltimore Longitudinal Study of Aging (BLSA) [16] and a study from our group on ~1500 participants (51% women) from the Trondelag Health Study (HUNT) in Norway [45] both included participants from a wide age range and reported data by ten-year age-groups. Although the estimated longitudinal declines from many of the longitudinal studies vary due to small samples and different inclusion criteria ( Table 2, Fig. 2), the findings from the larger BLSA and HUNT studies show the same patterns with increasing declines in both absolute values (mL/kg/min) and percentage VO 2peak with higher age, with similar estimates for the declines (Fig. 3). The absolute decline for women in the HUNT Study seemed to level off after 60 years at about 15% decline per decade, but increased towards 20% per decade at high age in the BLSA. In men over 70 years of age the decline approached 25% per decade in both studies. Thus, the decline in both women and men is non-linear throughout life, but based on these two large studies it is clear that this is more pronounced in men than women. The mechanism or explanation for the apparent sex-differences in age-related declines in VO 2peak needs further study. Data from the randomized controlled Generation 100 Study following 1567 men and women age >70 years for five years showed annual declines in VO 2peak of about 2% after the first year of intervention for both the supervised exercise groups and the control group instructed in national physical activity recommendations. This equated to a 20% ten-year decline despite preserved exercise volumes throughout the study [51].

Fig. 1.
Cross-sectional reference data for VO 2peak by testing modality. Treadmill in the upper panel, and cycle ergometry in the lower panel. Each age-group corresponds to the given decade, not the exact age. Some data collected from graphs or adapted from similar age-groups.

Comparison of cross-sectional and longitudinal studies
The age-related decline estimated from cross-sectional studies compared to findings from the two large longitudinal studies reporting data by age-groups is shown in Fig. 4. When comparing cross-sectional and longitudinal age-related declines the estimates are similar in the middle-aged, but differ at higher age with longitudinal declines being consistently larger (Fig. 4). At younger ages the cross-sectional estimates tend to be higher. In addition to the longitudinal data from BLSA and HUNT presented in Fig. 3 only a few other studies have reported both longitudinal and cross-sectional data on VO 2peak in older adults over 60-70 years of age. Stathokostas et al. found 16% and 9% ten-year declines in 34 men and 28 women over 70 years of age, keeping in mind that the sample was relatively small. Also in this study cross-sectional declines were lower than longitudinal declines, although the difference was small in women. In the few studies reporting age-related declines in VO 2peak by both cross-sectional and longitudinal measures the mean longitudinal decline is consistently larger than the cross-sectional estimates [8,16,38,[40][41][42][43]45,47,50]. The only exception is the study by Jackson et al. [41] which may be explained by a large self-selection between the first and second measurement as only 10% returned to repeated testing as well as that the cohort itself consisted of highly selected and healthy National Aeronautics and Space Administration (NASA) employees mainly in their middle age. Also, they increased their activity level and decreased body mass during follow-up. Hollenberg et al. examined 592 adult men with a mean age 65 years with repeated measurements of VO 2peak over a minimum of three visits and a mean follow-up of 6.3 years [40]. In their repeated measures model they showed that the magnitude of estimates for longitudinal declines were consistently lower than for the cross-sectional estimates, with − 0.39 vs − 0.23 mL/kg/min/year for women, and − 0.69 vs − 0.34 mL/kg/min/year for men, in line with the findings from BLSA and HUNT.

Explanations for the discrepance between cross-sectional and longitudinal studies
The discrepancy between findings using cross-sectional and longitudinal designs is likely to stem from issues regarding selection and survivor bias (i.e. those living until older age most likely were healthier in their younger years than those becoming ill or dying at a younger age). This is especially important given the strong associations between VO 2peak and numerous health outcomes, including longevity. This will have a pronounced effect in older ages as the selection pressure due to disease, ailments, and declining PA levels most likely will lead to superhealthy older adults participating in cross-sectional studies. In longitudinal studies this will also theoretically lead to some underestimation of the true age-related decline, as one would expect sicker individuals to experience faster declines in VO 2peak and also have a higher risk of mortality or other disease limiting participation in studies requiring maximal exercise to measure CRF. Thus, due to the strong association to health-outcomes for VO 2peak and the described survivor bias it is likely that a participant in its eight decade in a cross-sectional study on average would have had higher VO 2peak than a 30-year-old in the same study when at the same age, as pointed out also by Fleg et al. [16]. Similarly, cohort effects may play a role in explaining lower declines found in cross-sectional studies. This is evident as studies have shown how CRF has declined on the populational level over the last decades for example in the adult Swedish workforce [52], US youth [53], and children and adolescents from 19 different high-income and upper   middle-income countries [54]. Also, the same trend has been shown in US adults from the 1970s to the 2000s, with some evidence of an increase in the 2010s, with these trends linked to changes in body mass index [55]. Pooled data from eight high-and upper-middle-income countries showed a 1.6% decline in CRF per decade from the 1960s until 2016 [56]. Longitudinal, repeated observations are therefore necessary to obtain reliable estimates on declines in VO 2peak associated with aging [11,16,38]. Aging itself, but also increasing risk of ceasing or reducing physical activity with higher age is possible explanations behind the accelerating decline in VO 2peak with higher age, although this is still not well understood. Based on e.g. longitudinal studies on athletes Hawkins and Wiswell proposed that not only aging itself but inability to maintain exercise training with higher age is also responsible for the accelerated decline seen at older age [11]. Although not elaborated on here it should be noted that statistical model choices and artifacts from various models may also explain differences between crossectional and longitudinal designs [57]. The differences in sample sizes between cross-sectional and longitudinal studies should be kept in mind as well when interpreting differences across these designs. Furthermore, there is also a lack of data regarding differences across ethnicities. These limitiations highlight some of the further research opportunities in the field.

Clinical implications and concluding remarks
Age is a strong determinant of CRF, and the decline in CRF increases with higher age to 15-20% per decade for women and 20-25% per decade for men after 70 years of age. Age-related declines are consistently larger from longitudinal studies compared to cross-sectional studies possibly due to survivorship bias in the latter. When following patients over time and interpreting trajectories of CRF one should make these assessments in light of findings from longitudinal studies, and not only from findings in cross-sectional studies.

Author statement
JML designed the study, performed analyses and data visualization, and drafted the first draft. BMN and UW designed the study and revised the draft.

Funding
The work was funded by The Liaison Committee for Education, Research and Innovation in Central Norway. There are no relations to industry associated with this work.

Declaration of competing interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.